Alzheimer's disease (AD) is characterized by extensive neuronal death in the cerebral cortex. This loss of neurons is correlated with the severe functional decline in cognition and memory observed in AD patients. Neuropathological changes restricted to the hippocampal formation are a consistent reflection of age-related memory impairment, but overt dementia is present only in cases with neocortical involvement. Distinct subpopulations of neocortical neurons undergo severe degeneration in AD, while others are remarkably preserved even at late stages of the disease. Thus, in association neocortical areas a subset of pyramidal neurons are particularly vulnerable in AD, while other neuron classes remain viable throughout the progression of AD. The vulnerable neurons are all characterized by their large size, their extensive dendritic arborization and their relatively high content of neurofilament protein. Further investigations have demonstrated that these neurons are also involved in neurofibrillary tangle (NFT) formation and that there exist age-related shifts in the expression of neurofilament protein and other molecules, such as glutamate receptor subunit proteins (GluRs), that may render a neuron prone to neurodegeneration. However, the degree to which molecular and morphological alterations restricted to identifiable neuronal populations represent reliable thresholds reflecting early degeneration or functional deficits has not yet been determined. This component is designed to analyze quantitatively the molecular and morphologic correlates or functional decline and the progression of neuronal alterations in the superior frontal cortex of AD cases by developing quantitative indices of neurofibrillary degeneration (INDs) based on ratios of stereologic estimates of neurons and NFTs in the superior frontal cortex. We will also determine quantitatively the complement of GluRs in identified sets of corticocortical projections linking the prefrontal cortex to temporal and parietal association areas in the macaque monkey to test the hypothesis that substantial differences exist in the distribution of key GluRs among the neurons of origin of these projections. Based on this prediction, we will investigate whether the neurons at risk in AD exhibit overall low staining intensity for the AMPA subunit GluR2 and that progressive shifts in AMPA and NMDA subunits expression will take place as neurons undergo degenerative changes. We hypothesize that a decrease in GluR2 staining intensity will be concomitant of the appearance of the earliest degenerative neuronal changes in AD, in a selected population of neurons, but that no such association will be observed with NMDAR1. The detailed quantitative data obtained from these studies will provide crucial information on the anatomic and neurochemical determinants of selective neuronal vulnerability in AD.